functionalfoodsandnutraceuticalsintheprimary...

Hindawi Publishing CorporationJournal of Nutrition and MetabolismVolume 2012, Article ID 569486, 16 pagesdoi:10.1155/2012/569486

Review Article

Functional Foods and Nutraceuticals in the PrimaryPrevention of Cardiovascular Diseases

Eman M. Alissa1 and Gordon A. Ferns2

1 Faculty of Medicine, King Abdul Aziz University, P.O. Box 12713, Jeddah 21483, Saudi Arabia2 Faculty of Healthand Institute of Science & Technology in Medicine, Keele University, Staffordshire ST4 7QB, UK

Correspondence should be addressed to Eman M. Alissa, em [email protected]

Received 14 December 2011; Accepted 16 February 2012

Academic Editor: A. Venketeshwer Rao

Copyright © 2012 E. M. Alissa and G. A. Ferns. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Cardiovascular disease (CVD) is now the leading cause of death globally and is a growing health concern. Dietary factors areimportant in the pathogenesis of CVD and may to a large degree determine CVD risk, but have been less extensively investigated.Functional foods are those that are thought to have physiological benefits and/or reduce the risk of chronic disease beyond theirbasic nutritional functions. The food industry has started to market products labelled as “functional foods.” Although many reviewarticles have focused on individual dietary variables as determinants of CVD that can be modified to reduce the risk of CVD, theaim of this current paper was to examine the impact of functional foods in relation to the development and progression of CVD.Epidemiologic studies have demonstrated the association between certain dietary patterns and cardiovascular health. Research intothe cardio-protective potential of their dietary components might support the development of functional foods and nutraceuticals.This paper will also compare the effect of individual bioactive dietary compounds with the effect of some dietary patterns in termsof their cardiovascular protection.

1. Introduction

Cardiovascular disease (CVD) is now the leading causeof death globally and is a growing health concern [1].Lifestyle-related conditions, such as obesity, hyperlipidemia,type 2 diabetes, and hypertension, are also widespreadand becoming more prevalent globally [2]. Although thetraditional cardiovascular risk factors (Table 1) have beenextensively investigated, dietary factors are also important inthe pathogenesis of CVD and may to a large degree determineCVD risk factors such as blood pressure and dyslipidaemia,but have been less extensively investigated.

The role of dietary factors has been largely investigated byreducing the content of specific food component known toincrease risk, that is, sodium or saturated fats [3] or by largelongitudinal cohort studies in which baseline dietary intakewas related to cardiovascular outcomes [4, 5].

The term “functional foods” has been commonly usedin marketing but still lacks a firm regulatory definition[6]. Functional foods are those that are thought to have

physiological benefits and/or reduce the risk of chronicdisease beyond their basic nutritional functions [7]. The foodindustry has started to market products with a “functionalfood” label. Whilst the benefits of some functional foodconstituents may be perceived to enhance short-term well-being, the benefits are generally related to the long-termmitigation of certain diseases.

Although many review articles have focused on individ-ual dietary variables as major determinants of CVD that canbe modified in order to reduce the risk of CVD, the aim ofthis current paper was to examine the impact of functionalfoods in relation to the development and progression ofCVD. Epidemiologic studies have long demonstrated theassociation between certain dietary patterns and cardiovas-cular health. Research into the cardioprotective potentialof their dietary components may support the developmentof functional foods and nutraceuticals. This paper willalso compare the effect of individual bioactive dietarycompounds with the effect of some dietary patterns in termsof their cardiovascular protection.

2 Journal of Nutrition and Metabolism

The antioxidant

defense systems

Dietary

antioxidant

nutrients

Endogenous

enzymatic

antioxidants

Superoxide dismutase,

catalase, glutathione,

peroxidase

Water solubleascorbic acid,

flavonoids, trace

elements (selenium,

copper, zinc, chromium,

manganese)

Lipid solublecarotenoids

lutein, zeaxanthin,

cryptoxanthin),

-tocopherol

(β-carotene,

β-

α-carotene, lycopene,

α

Figure 1: The antioxidant defense system comprise, endogenous enzymatic and exogenous nonenzymatic nutrients. The dietary antioxidantnutrients can either be water soluble or lipid soluble. There are also other dietary constituents that may have either direct antioxidant activityor indirect antioxidant activity such as trace elements that are constituents of antioxidant enzymes.

Table 1: Cardiovascular risk factors.

Category Examples

Nonmodifiable riskfactors

Advancing ageMale genderFamily history/genotype

Metabolic risk factors

HypertensionHyperlipidemiaDiabetes mellitusMetabolic syndromeObesity/overweight

Lifestyle risk factorsDietSmokingPhysical activity

Novel risk factors

Elevated homocysteine levelElevated lipoprotein (a) levelSmall dense LDL-CElevated inflammatory markers levelsElevated hemostatic factors levels

2. The Protective Effect of Diet in CVD

It has been proposed that CVD can be prevented by lifestylechanges, including diet [8]. Early evidence for the role of dieton CVD came from data on trends in food consumption,and ecological studies has shown associations between CVDprevalence and fat intake [3]. Moreover, excessive con-sumption of foods that are caloriedense, nutritionally poor,highly processed, and rapidly absorbable can lead to systemic

inflammation, reduced insulin sensitivity, and a cluster ofmetabolic abnormalities, including obesity, hypertension,dyslipidemia, and glucose intolerance [9]. More recently,there has been a focus in nutrition research to try andunderstand the effects of whole foods [10]. An integratedapproach combining lifestyle modification with the correctpharmacologic treatment is sought to reduce cardiovascularrisk factors, to improve vascular health, and to reducehealthcare expenditure [11].

Whilst epidemiological studies have identified a rela-tionship between diet and CVD, there is still considerablescientific uncertainty about the relationship between specificdietary components and cardiovascular risk. Observational,prospective cohort studies suggest that a higher dietaryintake or supplementation of antioxidants is associated witha lower risk of CVD and mortality, but the evidence fromclinical trials is still largely negative [12]. The conflictingresults between the apparent protective effects of nutrientsas part of dietary intake and the lack of effectiveness of singlenutrient supplementation in trials has led to a focus on wholefoods or modified diets as protective against CVD [13].

Oxidative stress may be defined as a disturbance in thepro-oxidant/antioxidant balance that favours oxidation. Ithas been suggested that oxidative stress is involved in theetiology of several chronic diseases including CVD, diabetes,stroke, some cancers, and neurodegenerative disorders [14].Dietary nutrients, both water soluble and lipid soluble,comprise an important aspect of the antioxidant defensesystem (Figure 1).

Journal of Nutrition and Metabolism 3

Beyond their normal occurrence in cells and tissues ofliving organisms, free radicals and reactive species are alsoproduced in the foods people consume every day, inducingundesirable reactions like oxidation of lipids, proteins,nucleic acids, and carbohydrates.

An impaired capacity to scavenge free radicals andreactive species as a consequence of decreased levels ofantioxidant cellular defense systems or excessive free radicalsproduction is common in brain, liver, heart, and otherimportant target organs in humans and animals [15, 16].

It was initially thought that antioxidant vitamins wouldhave represented a simple approach to counteract increasedoxidative stress by cardiovascular risk factors. Nonetheless,high doses of some antioxidant vitamins were found toexert adverse vascular effects. The effects of antioxidantsupplements on all-cause mortality of adults included inprimary and secondary prevention trials, by treatment withbeta carotene, vitamin A, and vitamin E, may indeed increasemortality, and the potential role of vitamin C and seleniumon mortality needs further study [17, 18].

3. Functional Foods

The notion that foods not only provide basic nutritionbut can also prevent diseases and ensure good healthand longevity is now attained greater prominence [19].Various terms have been used interchangeably to designatefoods for disease prevention and health promotion. Theterm Nutraceuticals was introduced in 1989 by the USFoundation for Innovation in Medicine and referred to “anysubstance that is a food or a part of a food and providesmedical or health benefits, including the prevention andtreatment of disease” [20]. The interest in nutraceuticalsfor cardiovascular prevention was particularly stimulatedafter the observations of a close association between theconsumption of particular dietary factors, as indicated byhigher plasma levels [21, 22], and a reduced cardiovascularevent rate. In 1994, the US Institute of Medicine’s Food andNutrition Board defined functional foods as “any food orfood ingredient that may provide a health benefit beyond thetraditional nutrients it contains” [6, 7, 23].

4. Functional Foods withHealth-Related Properties

The conflicting results between the apparent protectiveeffects of nutrients as part of entire food intake and thelack of effectiveness of single nutrient supplementation intrials has led to a focus on whole foods as protectiveagainst CVD. Populations consuming a large proportion ofplant-based foods, including fruits and vegetables, or thosewith high intake of seafood are known to have a lowerincidence of CVD and certain types of cancer [24]. Basedon these findings, considerable interest has been expressedby manufacturers, consumers, and health professionals infunctional foods and nutraceuticals.

Functional foods, containing physiologically active com-ponents either from plant or animal sources, marketedwith the claim of their ability to reduce heart disease risk

focusing primarily on established risk factors, that is, bloodcholesterol, diabetes, and hypertension. Functional foodsare suspected to exert their cardioprotective effects mainlythrough lipid lowering effects, antioxidant actions, and/ordecreased homocysteine levels (Table 2).

Vegetable and fruit fibers (with pectin), garlic and oilyseeds (walnut, almonds, etc.), and fish oils have lipid-lowering effects in humans, through both inhibition of fatabsorption and suppression of hepatic cholesterol synthesis.Homocysteine increases the risk of both cardiovascularand cerebrovascular disorders [25] by enhancing arteriolarconstriction and decreasing endothelial vasodilation [26]. Ahigher intake of folate, antioxidant vitamins, whole grains,and phytochemicals has been reported to abrogate thedeleterious vascular effects of homocysteine in the heart [27,28]. A significant cardiovascular benefit of phytochemicals(polyphenols in wine, grapes, and teas), vitamins (ascorbate,tocopherol), and minerals (selenium, magnesium) in foods[19, 29] is thought to be the capability of scavenging freeradicals produced during atherogenesis.

Several functional foods are thought to be of benefit intreating and preventing CVD. The most common functionalfoods that have been studied in cardiovascular patients arelong-chain n-3 fatty acids, dietary fiber, and phytochemicalsas well as nutrients based on or enriched with vegetableproteins, mainly soy.

4.1. Fish. People with a high intake of dietary fish and fish oilsupplements have a low rate of CVD [30, 31]. Although fishper se contains various nutrients with potentially favourableeffects on health, attention has been particularly focused onthe omega-3 (n-3) fatty acids. n-3 fatty acids also include theplant-derived alpha-linolenic acid (ALA, 18 : 3 n-3), eicosa-pentaenoic acid (EPA, 20 : 5 n-3), and docosahexaenoic acid(DHA, 22 : 6 n-3). Both EPA and DHA are found in oilyfish, such as salmon, lake trout, tuna, and herring, and fish-derived products (fish oils). n-3 fatty acids precursor, α-linolenic acid, is typically found in various plants (e.g., spin-ach), seeds (nuts and flaxseeds), and oils derived from them.Generally, very little ALA is converted to EPA, and even less toDHA, and therefore direct intake of the latter two is optimal.

Despite the established beneficial effect of fatty fishconsumption on CHD, the species and amount of fishconsumed, as well as the preparation method, have an impacton CHD risk [32]. The concomitance of low amounts of n-3fatty acids in our average diet and the need for prolongedadministration for prevention and treatment has led tothe development of selected preparations (enriched foodsor special formulations, e.g., n-3 fatty acids incorporatedinto cows’ milk). These should combine acceptability andadequate bioavailability of their relatively low contents of n-3fatty acids. These fatty acids are therefore being incorporatedinto a number of commercially available, natural foods that,due to rather their structural features, appear to be partic-ularly suited as efficient fatty acid vehicles [33]. Further-more, some environmental contaminants found in certainfish, for example, methylmercury, polychlorinated biphenyls,and dioxins, may diminish the health benefits of fish-derivedn-3 fatty acids [34].


Table 2: Potential cardiovascular protective effects of functional foods.

Functional foods Bioactive compounds Potential mechanism References

- Nuts- Tocopherols, omega-3 fattyacids

Lowering blood cholesterol

Sabate and Ang [60]Albert et al. [62]

- Legumes - Fiber and polyphenols Erkkila and Lichtenstein [55]

- Fruits and vegetables - Fiber (pectin) Liu et al. [56]

- Margarine - Phytosterols Darmadi-Blackberry et al. [63]

- Fish oil - Omega-3 fatty acids Hicks and Moreau [110]

- Whole grains - Fiber and phytochemicals Dyerberg et al. [37]

- Soy proteins - Genistein and daidzein Lutsey et al. [73]

- Dark chocolate - Flavonoid

Anderson et al. [78]Harland and Haffner [79]Grassi et al. [89]Baba et al. [90]

- Fish - Omega-3 fatty acids

Inhibition of LDL-Coxidation

Lee and Wander [39]

- Green leafy vegetables, fruits - Carotenoids Chopra et al. [52]

- Citrus fruits and vegetables - Vitamin C Sesso et al. [119]

- Tomato - Lycopene Aguirre and May [115]

- Extravirgin olive oil - Polyphenolics and oleic acid Engelhard et al. [123]

- Green tea - Tea polyphenolics Psaltopoulou et al. [145]

- Soy proteins- Genistein, daidzein, andglycitein

Wiseman et al. [81]

- Dark chocolate - Flavonoid Grassi et al. [89]

- Pomegranate - Polyphenols Davidson et al. [99]

- Fish - Omega-3 fatty acids Lowering blood triglyceridesDurrington et al. [36]Dyerberg et al. [37]Harris et al. [40]

- Fish - Omega-3 fatty acids Mozaffarian [35]

- Legumes - Fiber He et al. [53]

- Whole grains - Fiber and phytochemicalsSavica et al. [54]Lee et al. [65]

- Citrus fruits - Ascorbic acid Flint et al. [72]

Decreasing blood pressure

- Ginseng - Ginsenosides

Hooper et al. [108]

- Onion and garlic - Quercetin

- Green and black teas - Tea polyphenols

- Grapes and red wines - Grape polyphenols Perez-Jimenez and Saura-Calixto [160]

- Dark chocolate- Flavonoid

Grassi et al. [89]

- Fruits and vegetables- Folate- Phytochemicals

Lowering bloodhomocysteine

Samman et al. [144]Appel et al. [152]

- Whole grains - Fiber and phytochemicals Jenkins et al. [154]

- Citrus fruits and vegetables - Vitamin C Broekmans et al. [27]

- Nuts, seeds, and oils - Vitamin E

- Tomatoes - Lycopene

Antioxidant action

Engelhard et al. [123]Krinsky and Johnson [121]Sesso et al. [119]Aguirre and May [115]

- Green leafy vegetables, fruits - Carotenoids

- Vegetable oils - Tocopherol, tocotrienols

- Citrus fruits and vegetables - Vitamin CMink et al. [105]Perez-Jimenez andSaura-Calixto [160]

- Soy proteins - Genistein and daidzein

- Green and black teas - Tea polyphenols

- Grapes and red wines- Anthocyanins, catechins,cyanidins, and flavonols,myricetin and quercetin


Table 2: Continued.

Functional foods Bioactive compounds Potential mechanism References

- Nuts, seeds, and oils - Vitamin EAnti-inflammatory action

Singh et al. [128]Kushi et al. [130]

- Fish - Omega-3 fatty acids Ueeda et al. [38]

- Legumes - Polyphenols Lutsey et al. [73]

- Grapes and red wines- Anthocyanins, catechins,cyanidins, and flavonols,myricetin, and quercetin

Perez-Jimenez and Saura-Calixto [160]

- Fish - Omega-3 fatty acids

Endothelial function

Ueeda et al. [38]

- Nuts - Polyphenols Ros et al. [61]

- Citrus fruits and vegetables - Vitamin C Aguirre and May [115]

- Grapes and red wines- Anthocyanins, catechins,cyanidins, and flavonols,myricetin, and quercetin

Perez-Jimenez and Saura-Calixto [160]

- Dark chocolate - Flavonoid Grassi et al. [88]

- Grapes and red wines- Anthocyanins, catechins,cyanidins, and flavonols,myricetin and quercetin

Platelets aggregationPerez-Jimenez and Saura-Calixto [160]Mink et al. [105]

Potential mechanisms for the cardiovascular protec-tive effects of n-3 fatty acids are suggested to be; anti-inflammatory, antithrombotic (reduced platelet aggregabil-ity), and antiarrhythmic (reducing the risk of potentiallyfatal cardiac arrhythmias), lowering of heart rate and bloodpressure, hypotriglyceridemic, and improved endothelialfunction [35].

Fish oil supplements have favorable effects on lipidprofile and blood pressure [36, 37]. The former appearsto be due to decreased hepatic triglyceride secretion com-bined with enhanced clearance of triglycerides from plasma.Moreover, fish ingestion has been related to a reduced riskfor myocardial infarction, which may relate to beneficialeffects of EPA and DHA on plaque stability (probably relatedto the content of inflammatory cells) and modulation ofendothelial function [38]. EPA and DHA have also beenshown to lower low-density lipoprotein (LDL) oxidativesusceptibility in postmenopausal women, which could helpto reduce the risk of CVD [39]. Primary among these isthe reduction of serum triglycerides [40]. While researchinterests in the effects of n-3 fatty acids have been focusedmainly on the long-chain compounds (EPA and DHA), therole of n-3 ALA should also be considered. Data on the effectsof ALA on CVD outcomes are somewhat limited [41, 42], assome researchers suggest potential cardiovascular protectionby this unsaturated fatty acid [43].

A meta-analysis of 65 studies demonstrated that n-3fatty acids lowered triglycerides levels in a dose-dependentmanner, with the triglycerides lowering being proportionalto baseline levels [44]. However, the data demonstrate a largeinterstudy variability in response to the treatment that ispossibly due to the dose or ratio of n-3 fatty acids, the dura-tion of study, the health status, diet, and other confoundingfactors. The large heterogeneity within studies with n-3fatty acids supplementation for the response to triglyceridesis likely to be attributable to genetic variability within thestudy population. Nevertheless, these intervention studies

are largely short term and involved frequently higher dose ofn-3 fatty acids as compared to the clinical outcome studies.Furthermore, more studies are needed to determine whetherthere exist specific genotypes that may benefit to a greaterextent from n-3 fatty acids for hypotriglycerolaemic effects.Clinical studies also need to determine whether the reductionin CVD risk factors is due to EPA, DHA, or the combinationof both and the dosage of the effective components[31].

4.2. Fruit and Vegetables. There is a substantial amount ofliterature that has consistently reported the beneficial effectsof diets rich in vegetables and fruits on CVD risk [45–48].Conversely, inadequate consumption of fruit and vegetableshas been linked with higher incidence of CVD [49]. Thebenefits of fruit and vegetable intake appear to be doserelated. In addition, frequency of fruit and vegetable intakehas been associated with lower CVD risk [50, 51].

The mechanisms by which fruit and vegetables exerttheir protective effects are not entirely clear but likelyinclude antioxidant and anti-inflammatory effects. Amongthe possible explanations for this beneficial effect, fruitsand vegetables have been found to decrease susceptibility ofLDL particles to oxidation [52]. Potassium may also havea protective role on the incidence of CVD as mountingevidence indicates an inverse association between dietaryintake of fruits and vegetables and blood pressure [53,54]. Several bioactive components in fruits and vegetablessuch as carotenoids, vitamin C, fiber, magnesium, andpotassium act synergistically or antagonistically to promote aholistic beneficial effect. The totality of the evidence supportscurrent dietary guidelines to increase fruit and vegetableconsumption to at least five.

Soluble fibres including pectins from apples and citrusfruits, β-glucan from oats and barley, and fibres fromflaxseed and psyllium are known to lower LDL-C [55].The mechanisms of their cholesterol-lowering effects are


suggested to be the binding of bile acids and inhibition ofcholesterol synthesis. However, in the Health ProfessionalsFollow-Up Study, only cereal fiber, not fruit or vegetablefiber, was inversely associated with risk of total stroke [56].

In contrast, several studies have not seen significant pro-tective effects of fruit and vegetables on mortality, althoughmost show protective trends. These include a study of adultsin Maryland [57], the Kuopio Ischaemic Heart Disease RiskFactor (KIHD) study among middle-aged Finnish men [58],and the Adventist Health Study [59]. These studies may havehad insufficient power, or inadequate ranges of intake toobserve significant effects.

4.3. Nuts and Legumes. Nuts are complex foods containingcholesterol lowering mono- and polyunsaturated fatty acids,arginine (a precursor to the vasodilator nitric oxide), solublefiber, and several antioxidant polyphenols [60]. Postprandialvascular reactivity is characterized by decreased bioavail-ability of nitric oxide and increased expression of pro-inflammatory cytokines and cellular adhesion molecules[61]. It is not surprising that the evidence supporting thecardioprotective effects of diets high in nuts is robust asmultiple mechanisms work together to reduce risk. Prospec-tive data from the Physicians’ Health Study [62] indicatedreduced risk of sudden cardiac death associated with nutconsumption originally perceived as being unhealthy becauseof their high-fat content.

Legumes are also complex foods rich in soluble fibersand polyphenols, as well as folic acid. Legumes were theonly food group predictive of survival among five long-lived elderly cohorts in Japan, Sweden, Greece, and Australia[63]. Furthermore, cumulative evidence from experimentalresearch indicates that cholesterol-lowering effect of legumesare probably due to the combined effects of several bioactivecomponents, such as protein, soluble and insoluble fibres,and phytosterols [64]. A recent interventional trial inhumans has shown that lupin kernel flour added to bread hasalso a positive effect on blood pressure: both the fibre and theprotein were suggested to be responsible [65].

4.4. Whole Grains. Whole grain products contain intactgrain kernels rich in fiber and trace nutrients. They arenutritionally more important because they contain phy-toprotective substances that might work synergistically toreduce cardiovascular risk.

The potential protective role of whole grains was firstevaluated in the early 1970s [66]. Based on the results of theprospective Iowa Women’s Health Study that demonstratedcereal fiber had different associations with total mortality,depending on whether the fiber came from foods thatcontained primarily whole grain or refined grain [67].A more recent meta-analysis based on seven qualifyingprospective cohort studies focused on whole grain consump-tion and cardiovascular outcomes reported that the inverseassociation between dietary whole grains and incident CVDwas strong and consistent across trials [68–71].

The mechanisms underlying the protective effect ofwhole grains on CVD risk include its effects on insulin

sensitivity [28], blood pressure [72], lipids, and inflamma-tion [73]. Although the anti-inflammatory mechanism isnot clear, it may be related to higher intakes of antioxidantnutrients present in the germ of whole grains. As comparedto refined grains, whole grains have a reduced glycemicresponse following ingestion (i.e., the postprandial rise inblood glucose is lessened), and reductions in postprandialglucose surges have been associated with reduced reactiveoxygen generation after a meal and reduced postprandialinflammation and CVD risk [28].

4.5. Soy Proteins. Soy is the main source of protein in theJapanese diet, consumed in the form of miso soup and tofu.Soy products are rich in polyunsaturated fatty acids, fiber,vitamins and minerals, and low saturated fat content [74].

Prospective observational studies, initially in vegetarians[75], then in Chinese women [76], and in a Japanesepopulation [77], have shown a reduction of total cholesteroland LDL-C as well as of ischaemic and cerebrovascular eventswith a daily soy protein intake of more than 6 g, comparedwith less than 0.5 g. A large number of clinical studieswere summarized in a meta-analysis [78] and confirmedthat serum LDL-C concentrations are modified, the effectsbeing related to baseline blood cholesterol levels. The resultsof this meta-analysis were criticized recently, since morerecent studies appeared not to confirm the very powerfulcholesterol-reducing effect of soy proteins [74]. A recentsystematic review of available randomized controlled studiesmainly in subjects with moderate hypercholesterolaemiaconfirmed that the inclusion in the diet of a modestamount of soy protein (25 g) produces a highly significantreduction of total cholesterol and LDL-C levels equivalentto ca. 6% LDL reduction [79]. Old studies were basedon the effects in severely hypercholesterolaemic individuals,whereas patients with hypercholesterolaemia in the veryhighest range (>3350 mg/L) have not been selected fortreatment in recent studies.

Soy products contain many isoflavonoids (genistein,daidzein, glycitin) that are natural phytoestrogens able toinhibit LDL oxidation, thus decreasing the risk of athe-rosclerosis [80]. Several studies have reported a decreasein susceptibility of LDL particles to oxidation with soyprotein consumption [81]. Furthermore, soy protein rich inisoflavones reduced the susceptibility of LDL particles to oxi-dation in healthy subjects [82]. Meta-analyses of randomizedcontrolled trials have shown that soy isoflavones can lowerserum total and LDL cholesterol in humans [83]. The efficacyof soy foods and isoflavone supplements on blood lipidsin clinical trials is less clear. These contradictory data maybe due to poorer responses in hypercholesterolemic subjectscompared to their control counterparts [74]. Recent clinicaltrials in postmenopausal women with soy protein have alsoshown similar discrepancies [84]. Clearly additional studiesare needed to determine whether there are differences amongwhole food, soy protein and isoflavone extracts.

Comparisons between different animal or clinical stud-ies are hampered by the lack of standardization of soynomenclature, the different formulations, doses, routes ofadministration, time, and duration of exposure [85].


4.6. Dark Chocolate. Cocoa is a flavonoid-rich food that hasbeen recently investigated for its possible role in the preven-tion of CVD [86, 87]. In healthy adults, drinking flavonoid-rich cocoa may improve NO-dependent vasorelaxation andflow-mediated dilation in the brachial arteries [88]. Admin-istration of dark chocolate in essential hypertensives reducedambulatory blood pressure and serum LDL-C levels whereaswhite chocolate had no effects [89]. Furthermore there wasa clear reduction of the blood cholesterol levels as well as asignificant rise of HDL cholesterol in addition to a markedreduction of circulating oxidized LDL [90].

4.7. Coffee and Tea. The active constituents of coffee appar-ently responsible for cardioprotective effect are diterpenes,such as kahweol and cafestol. Coffee consumption maypossibly reduce the risk of myocardial infarction, but dataare as yet inconclusive [91, 92]. A dose-response decrease incardiovascular risk and heart disease mortality was reportedfor a daily caffeine intake in patients with type 2 diabetes[93, 94].

Green tea consumption appears to protect from CVD[95], but results are again inconsistent. It has been reportedin a meta-analysis that the incidence of myocardial infarctionamong individuals who consumed three cups of tea daily wasnot statistically significant and there has been large variabilityacross studies [96]. There were regional differences in thismeta-analysis, with increasing tea consumption associatedwith an increased risk for CHD in the United Kingdom andfor stroke in Australia, whereas the risk decreased in otherregions, particularly in continental Europe. The hypothesisthat addition of milk to tea (as typically done in UnitedKingdom and Australia) abolishes its plasma antioxidantpotential may only partially explain these geographic differ-ences.

5. Bioactive Dietary Compounds withCardioprotective Potentials

Early research evaluated the benefits of plant-derived foodsbased on their vitamin C, vitamin E, and carotenoid content[24]. More recent work pointed out correlation of benefitswith individual compounds [97]. However, the effects notedby testing them alone may be related to the synergisticaction of the myriad of other bioactives present in sourcematerials [98]. The main doubt about their efficacy, whetherthey should be consumed in a whole food diet or providedin a supplemental form remains to be answered and willbe discussed in what follows. In each family of bioactivecompounds there are usually many members that are presentas discussed in following.

5.1. Phytochemicals. Plant foods contain many bioactivecompounds known as “phytochemicals.” Some groups ofphytochemicals which have or appear to have signif-icant health potentials are carotenoids, phenolic com-pounds (flavonoids, phytoestrogens, phenolic acids), phy-tosterols and phytostanols, tocotrienols, organosulfur com-pounds, and nondigestible carbohydrates (dietary fiber and

prebiotics). Isoflavones are found in high concentrationin soybean, soybean products (e.g., tofu), and red clover.Lignans are mainly found in flaxseed.

5.1.1. Polyphenol Compounds. Polyphenols have been shownin in vivo studies to exert antiatherosclerotic effects in theearly stages of atherosclerosis development (e.g., decreaseLDL oxidation); improve endothelial function and increasenitric oxide release (potent vasodilator); modulate inflam-mation and lipid metabolism (i.e., hypolipidemic effect);improve antioxidant status; protect against atherothrom-botic episodes including myocardial ischemia and plateletaggregation (Perez-Jimenez and Saura-Calixto, 2008) [99].

5.1.2. Flavonoids. Plant-derived flavonoids are the mostcommon group of polyphenols in the human diet, and arecontained in vegetables and fruits as well as in beverages suchas cocoa, tea, and wine. Some isoflavones like lignans are phy-toestrogens, a group of nonsteroidal plant constituents thatelicit estrogen-like biological response. They are associatedas minor components with dietary fiber in dietary items likeoilseeds, cereal grains, vegetables, fruits, and legumes. Likeother phenolic compounds, phytoestrogens have antioxidantactivity, and like estrogens, they can influence lipoproteinmetabolism and enhance vascular reactivity.

Intake of flavonoids has been associated with decreasedcardiovascular mortality and general mortality amongelderly Dutch individuals [100]. Several prospective studieshave reported inverse associations between flavonoid intakeand CVD incidence or mortality [101–103]. Within thecardiovascular protective mechanisms of flavonoids, sev-eral mechanisms have been proposed to explain the anti-inflammatory properties of flavonoids. These include theirantioxidant activity and their properties as metal chelators,for transitional elements such as copper and iron thatcatalyze lipid oxidation; inhibitors of platelet aggregation;modulation of the activity of eicosanoid generating enzymesin inflammatory cells enhancers of nitric oxide synthesis;lowering of superoxide production; beneficial effects on lipidprofile [104, 105] and modulation of proinflammatory geneexpression [97, 106, 107].

A systematic review of the effectiveness of differentflavonoid subclasses and flavonoid-rich foods on CVD con-cluded that some flavonoid-rich foods, including chocolateor cocoa, red wine or grape, and green or black teamay have some measurable effects on CVD risk factors,including a reduction in blood pressure and a favorableinfluence on endothelial function [108]. Nevertheless, therestill exists uncertainty as to whether or not flavonoids are theonly bioactive compounds mediating the enhanced vascularreactivity. This is in part due to the fact that flavonoid-richfood and plant extracts contain many potentially bioactivecompounds, and information ensuing from investigationsin humans using specific, chemically pure flavonoids israre. Therefore, it cannot be completely excluded, that theobserved effects on vascular function may potentially, atleast in part, be related to compounds other than flavonoidscontained in these foods/extracts. It should be noted that noconclusive evidence has so far emerged about the therapeutic


efficacy of isoflavones in reducing the incidence of CVD andbreast cancer and in preventing the loss of bone mineraldensity in menopausal women.

5.1.3. Plant Sterols and Stanols. Plant sterols or phytosterolsare structurally similar and functionally analogous to theanimal sterol, cholesterol. A less abundant class of relatedcompounds is the plant stanols or phytostanols, which arecompletely saturated forms of phytosterols. Dietary sourcesinclude vegetable oils, nuts, seed and grains, but the amountsare often not large enough to have significant cholesterol-lowering effects [109]. Also they have been incorporated infoods with higher fat content, such as spreads (margarines)and salad dressings. Phytosterols and phytostanols inhibitintestinal absorption of cholesterol [110]. HDL and/or VLDLwere generally not affected by stanols/sterols intake. Yet,effects of sterols/stanols on LDLs have been found to beadditive to diets and/or cholesterol-lowering drugs [111].This has been the basis for the development of phytosterol-enriched functional foods. Similar efficacy has been observedbetween plant sterols and stanols when they are esterified,which is the form added to foods [112]. Because plant sterolsand stanols can reduce fat-soluble vitamins, it is necessaryto consume plant sterols and stanols with an appropriateintake of fruit and vegetables, including carotenoids [113].There are also concerns about margarines containing plantsterols and stanols, related to the energy intake associatedwith consuming >2 g daily [114].

5.1.4. Vitamin C. The powerful antioxidant functions ofvitamin C serve to reduce tissue reactive oxygen speciesconcentrations, which in the atherosclerotic condition helpprevent endothelial dysfunction, inhibit vascular smoothmuscle proliferation, and reduce oxidized LDL cholesterol[115]. Several prospective studies have assessed the role ofvitamin C, both dietary and supplemental, in CVD, withmixed results [116]. Despite its role as an antioxidant,vitamin C has been identified as a pro-oxidant underconditions of high oxidative stress [117]. Most clinicaltrials have incorporated vitamin C into a mixture includingvitamin E and β-carotene, with largely null results in relationto CVD [118, 119]. Nutrients and bioactive compounds infoods act synergistically or antagonistically in the complexfood matrix to deliver the established health effects of foods.

5.1.5. Carotenoids. Carotenoids have been credited withother health-promoting effects: immune enhancement andreduction of the risk of developing degenerative diseasessuch as cancer, CVD, and cataract [120, 121]. These phys-iological activities have been attributed to an antioxidantproperty, specifically to the ability to quench singlet oxygenand interact with free radicals [122]. The carotenoids,particularly lycopene and beta-carotene, are other dietaryantioxidants that function to reduce oxidative stress in vivoand blood markers of inflammation [123]. Evidence fora role of carotenoids in CVD first stemmed from studiesthat showed that higher intakes of fruit and vegetableswere associated with lower risk of CVD [124]. However,studies on the association between dietary carotenoids and

CVD risk have been inconsistent. Women who regularly eatlarge amounts of lycopene, from tomato and derivatives,are less prone to developing CVD, since this phytochemicalhas the strongest antioxidant activities in the cardiovascularsystem [125]. Results from the KIHD study confirmed thatlower serum lycopene levels were associated with enhancedrisk of atherosclerosis in the common carotid artery [58].These protective associations were not evident for othercarotenoids like lutein, zeaxanthin, or β-cryptoxanthin[126]. Despite overwhelming evidence from epidemiologicalstudies on carotenoids role in CVD, clinical trials have failedto demonstrate a beneficial effect [18, 127].

5.1.6. Vitamin E. In addition to its role as a free radicalscavenger, vitamin E is a potent anti-inflammatory agent,especially at high doses [128]. Mounting evidence supportsthe strong inverse association between plasma vitamin E andCVD [129] as well as that between vitamin E intake and riskof CHD [130]. Nevertheless, clinical trials failed to supportthe role of vitamin E supplementation in preventing CVD[131]. Subsequent meta-analyses and systematic reviewsof more than 90 trials showed similar null results [132,133]. Most recently, a dose-response meta-analysis showedincreased risk of high-dose vitamin E (≥400 IU/day) on totalmortality [17]. There are many potential explanations forthese largely negative effects that include the use of the mostappropriate form and/or dose of vitamin E. This may beessential to obtain effective reduction of oxidative stress. Aswith carotenoids, the contrast between observational andinterventional studies results suggests that the protectiveeffects of α-tocopherol occur in the presence of othernutrients, and, therefore, it is most effective and safe whenobtained from foods.

5.2. Antioxidant Vitamin Supplementation. The term “dieta-ry supplement” can be defined as a product that is intendedto supplement the diet with one or more of the followingdietary ingredients: a vitamin, a mineral, a herb or otherbotanical, an amino acid, intended for ingestion in pill,capsule, tablet, or liquid form [134]. It should be noted thatnutraceuticals differ from dietary supplements in the follow-ing aspects: (1) nutraceuticals must not only supplement thediet but should also aid in the prevention and/or treatment ofdisease, and (2) nutraceuticals are used as conventional foodsor as sole items of a meal or diet [134].

In view of the detrimental role of free radicals and reac-tive oxygen species in the pathophysiology of atherosclerosis,supplementation with antioxidants (vitamins A, C, and E,folic acid, β-carotene, selenium, and zinc) was expected tobe protective. Some supplements (e.g., marine n-3 FAs andniacin) are effective in improving CVD risk factors, whereasothers (like B-vitamins: folate, vitamin B12, vitamin B6,antioxidants; vitamin E and selenium) despite promisingin vitro studies have shown little effect on CVD mortalityand morbidity, and antioxidant supplements may even haveadverse effects.

Epidemiologic studies have reported that a high dietaryintake of foods rich in vitamin E [21], vitamin C [135],and β-carotene [126] have been inversely associated with


the incidence of CAD. Nevertheless, firm recommendationsto take antioxidant supplements to treat or prevent CVDor metabolic diseases require evidence derived from ran-domized controlled trials with vitamin supplements, whichwere found to be disappointing [136]. Indeed, only one trialhas shown a reduction in myocardial infarction and cardiacevents [137], whereas all the others have shown no effector detrimental effects. Within five trials, such antioxidantsupplementation was associated with increased all-causemortality and two have shown higher risk of fatal CHD(ATBC and CARET). Indeed, those controversial results byno means invalidate the role of oxidative stress in CVD;rather, they suggest that very high supplementation withantioxidant vitamins may not represent an optimal strategyto prevent vascular damage induced by oxidative stress andlipid oxidation. Several factors ought to be considered, whichmay have contributed to cloud the results of clinical trials,like choosing the optimal dose and form of vitamins, the useof single vitamin(s) or in combination, and so forth [138].

6. Dietary Patterns and Reduced Risk ofChronic Diseases

Eating habits and dietary trends have health, environmental,and social impacts. Some diet plans demonstrated the abilityto reduce cardiovascular risk [139]. Despite the high levelsof interest in the diet and health relationship, the traditionalapproach in nutritional epidemiology has mainly focusedon the effects of individual nutrients or foods. However,individuals do not consume nutrients in isolation but, rather,meals consisting of a variety of foods in combinations ofnutrients that are likely to be interactive or synergistic.Indeed much less concern has been focused on dietarypatterns because of their complex nature. The mechanismsby which these diets reduce inflammatory risk are notwell understood but may relate to high intakes of fooditems containing antioxidant nutrients and polyphenols thatreduce free radicals concentrations throughout tissues.

Consuming patterns of food vary significantly acrossnations, and this might contribute differently to the apparentdifferences in the health of populations on the continent.

6.1. Mediterranean Diet. The Mediterranean diets containhigh levels of fruits, vegetables, cereals, beans, nuts and seeds,and olive oil, with little red meat and dairy products. Fishand poultry are consumed in low-to-moderate amounts;and wine is consumed in moderation. They have receivedgreat attention and numerous reports have demonstratedlow rates of chronic disease among populations known toconsume these diets [140]. Moreover, clinical trials haveconfirmed their cardiovascular protective effects and theireffectiveness to reduce inflammatory markers in high-riskpopulations [13, 141, 142]. Several Mediterranean diet foods,including polyunsaturated fat products, vegetables, fruit,whole grains, legumes, and low glycaemic index starchyfoods with functional properties may protect against type2 diabetes [143]. They were also shown to reduce serumhomocysteine concentrations and consequently the risk of

coronary events, especially in high-risk individuals [144].Olive oil (which induces a high ratio of monounsaturatedto saturated lipids) appears to be chiefly responsible forthe apparent protection offered by the Mediterranean dietagainst hypertension [145]. The high antioxidant content ofplant foods and olive oil may also contribute to the healthof the vascular system. However, it has been indicated in arecent review that not all components of the Mediterraneandiet are equally protective [146]. Therefore, the convincingevidence for the protective role of the Mediterranean dietprovided by the Lyon Diet Heart Study [141] needs tobe replicated in primary prevention trials as well as theconduction in non-Mediterranean populations to determineif the favorable effects transfer to other groups.

6.2. DASH Diet. The Dietary Approaches to Stop Hyper-tension (DASH) trial reported that a diet rich in fish, fruit,vegetables, whole grains, and nuts and low in fat dairy foodssignificantly lowered systolic blood pressure in patients withisolated systolic hypertension [147]. This dietary pattern alsolimits saturated fat, red meat, sweets, and sugar-containingbeverages. Consistent weight loss induced by a very lowcaloric diet improves vasodilatation-mediated blood flow,an effect associated with decreased glucose blood levels[148]. Regular physical exercise, decreased salt (NaCl) intake,moderate alcoholic ingestion, and an increase in dietarypotassium constitute evidence-based strategies to reduceblood pressure by DASH diet.

Because hypertension is a CVD risk factor, severalprospective cohort studies have examined associationsbetween adherence to a DASH dietary pattern and incidentCVD events [10, 149, 150]. In addition to its effects onblood pressure and incident CHD, the DASH diet appears tohave beneficial effects on several CVD risk factors, includingtotal cholesterol, LDL-C [151], inflammation [149], andhomocysteine [152]. As a whole, the evidence for theprotective role of the DASH dietary pattern in prevention ofCVD is strong.

6.3. Portfolio Diet. Step I and Step II diets are early examplesof dietary strategies recommended for the clinical manage-ment of high blood cholesterol [153]. The Step I diet requiresa total fat intake of less than 30% of total calories, withsaturated fatty acids contributing to less than 10% of totalcalories and cholesterol less than 300 mg/day. For individualswho require a more aggressive approach to meet their LDL-C goals, the Step II diet, which lowers saturated fatty acidsto less than 7% of total calories and cholesterol to less than200 mg/day, is recommended.

Current recommendations for CVD risk reduction con-tinue to focus on LDL-C as a major therapeutic target.The National Cholesterol Education Program (NCEP) AdultTreatment Panel (ATP) III guidelines recommend therapeu-tic lifestyle changes for individuals whose LDL-C levels areabove goal (2001). LDL-C lowering can also be achieved byadding other dietary components, specifically plant sterols,viscous fibers, soy protein, and almonds. This combinationof dietary components has been labeled the Portfolio diet[154]. Another important attribute of the Portfolio diet is


its beneficial effects on C-reactive protein lowering, a strongindependent predictor of cardiovascular risk [155].

6.4. Vegetarian Diet. A vegetarian diet, devoid of meat andfish, and high in fruits, vegetables, and nuts, rich sourcesof the antioxidant nutrients and polyphenols, contributeto the anti-inflammatory potential of these diets. In termsof micronutrients content, vegan diets are usually higherin magnesium, folic acid, vitamins C and E, iron, andphytochemicals, and they tend to be lower in n-3 fattyacids, vitamin D, calcium, zinc, and vitamin B-12. Muchof this benefit is likely related to the low body weights, lowblood pressure, and low blood cholesterol concentrationsgenerally observed for vegetarians due to their lower intakesof saturated fats, cholesterol, and calories. Vegetarians arereported to have a lower risk of dying from ischemic heartdisease [156] and have a reduced all-cause mortality [57].

6.5. Okinawan Diet. Equally notable is the wide variationin other aspects of healthy diets such as macronutrientintake, represented most notably by the healthy Okinawandiet, which is low in fat and high in carbohydrates (mostlyfrom vegetable sources). This suggests that low-energy,nutrient-dense diets with high-quality carbohydrates maybe beneficial for reducing the risk of CVD among manychronic diseases [157]. The cardioprotective benefit ofOkinawan diet is ascribed, in part, to the low consumptionof saturated fat. Other possible mechanisms, such as thehigh contents of phytochemicals, high antioxidant intake,and low glycemic load in this diet, are also likely to becontributing to decreased risk for CVD and some cancersthrough multiple mechanisms, including reduced oxidativestress. A comparison of the nutrient profiles of the previousdietary patterns shows that the traditional Okinawan diet isthe lowest in fat intake, particularly in terms of saturatedfat, and highest in carbohydrate intake, in keeping with thevery high intake of antioxidant-rich yet calorie-poor orange-yellow root vegetables, such as sweet potatoes, and green leafyvegetables [158]. The longevity of Okinawan populationssuggests that such a diet may even help to slow the agingprocess itself [159].

7. Conclusion

The relationship between dietary factors and CVD has beena major focus of health research for almost half a century.Epidemiological and clinical studies indicate that the riskof CVD is reduced by a diet rich in fruits, vegetables,unrefined grains, fish and low-fat dairy products, and low insaturated fats and sodium [11]. Other foods such as mono-and polyunsaturated fats, brans, nuts, plant sterols, and soyproteins have all been shown to have a favorable effect onlipid profile and blood pressure [9, 161].

Novel dietary approaches to cardiovascular preventionare of major significance in clinical research and practice.However, nutrition is a very complex research topic and itis not clear whether an individual component of the dietor a combination of nutrients and dietary habits may beresponsible for any cardioprotective effects. The advances

in the knowledge of both the disease processes and healthydietary components have provided new avenues to developdietary strategies to prevent and/or to treat CVD. It isnow evident, based on the extensive scientific evidence,that functional foods have broad ranging physiologic effectsin vivo that lessen inflammatory cascades and vascularreactivity. These effects are as powerful as pharmaceuticalinterventions, yet much safer. Although many of thesefunctional foods have been found to have high therapeuticpotential, future studies should include well-designed clini-cal trials assessing different combinations of these nutrientsto realize possible additive and/or synergistic effects onhealth outcomes. Many functional foods have antioxidantand anti-inflammatory activities, by mechanisms that mayrequire further investigation. Therefore, these functionalfoods should be incorporated into a healthy diet to providecardiovascular benefits and hence lower cardiovascular risk.

Emerging evidence for a potential role of antioxidantvitamins in atherosclerotic progression implies that theeffect of micronutrients is complex and not likely due to asingle nutrient in isolation. Therefore, the use of vitaminsupplements is not recommended. Rather, efforts should betargeted to increasing the consumption of vitamins-rich fruitand vegetables.

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